ROLE OF HSP 110 IN TAUOPATHY

HSP 110 在 Tauopathy 中的作用

• 批准号: 8394589
• 负责人: NAHID F MIVECHI
• 金额: --
• 依托单位: CHARLIE NORWOOD VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-10-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8394589
• 关键词: Acute Brain Injuries; Age; Alzheimer' s Disease; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Amyloid deposition; Appearance; Applications Grants; Axon; Behavioral; Brain; Brain Injuries; Caring; Cause of Death; Cells; Cerebrospinal Fluid; Cessation of life; Clinical; Cognitive; Complex; Development; Disease; Down Syndrome; Event; Exhibits; Exposure to; Family member; Future; Generations; Goals; Heat shock proteins; Impaired cognition; In Vitro; Inherited; Injury; Isomerase; Knowledge; Life; Location; Microtubule-Associated Proteins; Microtubules; Molecular; Molecular Chaperones; Molecular Machines; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Organism; Pathology; Patients; Pattern; Pick Disease of the Brain; Play; Production; Protein Dephosphorylation; Proteins; Records; Recovery; Risk; Role; Senile Plaques; Social Problems; Tauopathies; Testing; Tg2576; Therapeutic; Toxic effect; Traumatic Brain Injury; Variant; Veterans; Wild Type Mouse; age related; amyloid precursor protein processing; brain tissue; combat; corticobasal degeneration; disability; hyperphosphorylated tau; in vivo; mouse model; mutant; pre-clinical; prevent; protein degradation; protein misfolding; response; tau Proteins; tau aggregation

Potential Impact on Veteran's Heath care is that traumatic brain injury (TBI), which is the main cause of death and disability in people under 35 and a common occurrence in combat situations, leads to significant deficiency in cognitive and social problems and significant amyloid beta (A¿) generation. Furthermore, there is evidence of increased amyloid deposition and an increased risk of development of Alzheimer's disease (AD) following TBI. However, our knowledge regarding the treatment of AD is still incomplete. The neuropathological hallmarks of AD and other tauopathies include accumulation of senile plaques and/or neurofibrillary tangles (NFTs) that causes neurons to degenerate. Clinical records suggest that tau, which is localized in axons, plays a pivotal role in neurodegenerative disorders that are related to protein malfunction. Heat shock proteins (Hsps) such as Hsp110 and Hsp70i are highly expressed following exposure to environmental insults. Their role in neuronal disorders is supported by studies showing that several Hsps are components of NFTs. As such, Hsps have been detected in NFTs containing tau, in neuritic plaques of AD brain, and in the brain tissue following TBI. A direct indication of the role of Hsps in neurodegenerative disease is provided by our discovery that hsp110-/- mice exhibit an age-dependent accumulation of hyperphosphorylated tau (p-tau) and neurodegeneration. We have also found that Hsp110, tau, and Pin1 isomerase, whose deletion in mice leads to tauopathy are in the same complexes. Since the Hsp110 family member, Hsp70 has been shown to be involved in amyloid precursor protein (APP) processing in cells, we tested if hsp110-/- mice crossed with mice expressing a mutant APP (Tg2576+) exhibit accelerated pathology in vivo. Results indicate that indeed hsp110- /-Tg2576+ mice exhibit neuritic plaques at a younger age than the hsp110+/+Tg2576+ mice strongly suggesting a role for Hsp110 (and Hsp70i) in AD pathology in vivo. Therefore, understanding the mechanisms by which Hsp110 and Hsp70i prevent p-tau accumulation, reduce AD pathology, and impact TBI are the subject of this grant application. We hypothesize that Hsp110 and Hsp70i are critical for proper dephosphorylation of tau and are protective during AD and following TBI, and prevent neuronal death. In our proposed studies, we will determine the expression and intra-axonal localization of Hsp110, Hsp70i, tau, or if Hsp110 and Hsp70i are substrates of Pin1. As an example of neurodegenerative diseases associated with tauopathy, we will use hsp110-/-Tg2576+ mice to establish the role of Hsp110 complexes in APP processing and A¿ production in vivo; since the expression of Hsps increases following environmental insults and because TBI is known to increase the risk for developing AD, we will investigate if the presence of Hsp110 and Hsp70i play a role in the recovery from TBI, and if transiently increasing the levels of Hsps accelerate recovery following TBI; we will also examine the brain tissue sections from healthy or AD patients to determine the locations of Hsp110, Hsp70i in senile plaques; Finally, we will use cerebral spinal fluid (CSF) from the patients who have received TBI to determine whether the levels of Hsp110 or Hsp70i following injury correlates with the extent of brain injury.

对退伍军人卫生护理的潜在影响是脑外伤（TBI），这是死亡的主要原因 和35岁以下的人的残疾以及在战斗情况下发生的常见发生，导致严重的缺陷 在认知和社会问题以及重要的淀粉样β（A�）一代中。此外，还有证据 淀粉样蛋白沉积的增加和阿尔茨海默氏病发展的风险增加（AD） TBI。但是，我们对AD治疗的了解仍然不完整。神经病理学 AD和其他Tauopath的标志包括堆积老年斑块和/或神经原纤维缠结 （NFT）导致神经元退化。临床记录表明，在轴突中定位的tau播放 与蛋白质故障相关的神经退行性疾病中的关键作用。热休克蛋白 （HSP）在暴露于环境侮辱之后，高度表达了HSP110和HSP70I。他们的 研究表明，几个HSP是NFT的组成部分，在神经元疾病中的作用得到了支持。作为 这样的HSP已在包含Tau的NFT，AD脑的神经质斑块和脑组织中检测到了HSP 遵循TBI。我们的发现提供了直接指示HSP在神经退行性疾病中的作用 HSP110 - / - 小鼠表现出年龄依赖性的磷酸化tau（p-tau）和 神经变性。我们还发现HSP110，TAU和PIN1异构酶，其在小鼠中的缺失导致 to tauopathy处于相同的复合体中。由于HSP110家庭成员，HSP70已被证明是 参与细胞中淀粉样蛋白前体蛋白（APP）加工，我们测试了与小鼠交叉的Hsp110 - / - 小鼠 表达一个突变应用程序（TG2576+）在体内暴露的加速病理。结果表明确实是HSP110- /-TG2576+小鼠在年轻时暴露了与HSP110+/+ TG2576+小鼠的神经质斑块强烈建议 Hsp110（和Hsp70i）在体内AD病理学中的作用。因此，了解 HSP110和HSP70I可防止P-TAU积累，减少AD病理和影响TBI的主题 授予申请。我们假设Hsp110和Hsp70i对于适当的tau和磷酸化至关重要 在AD和TBI之后受到保护，并防止神经元死亡。在我们提出的研究中，我们将 确定HSP110，HSP70I，TAU或HSP110和HSP70I的表达和轴内定位 PIN1的底物。作为与tauopathy相关的神经退行性疾病的一个例子，我们将使用 HSP110 - / - TG2576+小鼠在体内建立HSP110复合物在App Processing和A的生产中的作用； 由于HSP的表达在环境伤害后增加，并且已知TBI增加 开发AD的风险，我们将调查HSP110和HSP70I的存在是否在恢复中发挥作用 从TBI，如果瞬时增加了HSP的水平，则TBI后加速了恢复；我们也会 检查健康或AD患者的脑组织切片，以确定HSP110，HSP70I的位置 老年斑块；最后，我们将使用已收到TBI的患者的脑脊髓液（CSF） 确定损伤后Hsp110或Hsp70i的水平是否与脑损伤程度相关。